The time course of health-related Quality of Life in rectal cancer patients undergoing combined modality treatment

Highlights • Prospective study on rectal cancer patients undergoing combined modality treatment.• HRQoL decreased over time during active combined modality treatment period.• HRQoL increased at one-year-after-surgery follow-up.• Physical and psychosocial factors differently weight on HRQoL at different phases.• Importance of psychological screening both after diagnosis and preoperative therapy.


Introduction
With around 700,000 new diagnoses per year, rectal cancer represents 30 % of colorectal cancers (CRC), which are the second most common type of cancer worldwide in terms of prevalence and cancerrelated mortality in both sexes [1].The stage of disease contributes to determine the specificities of treatments and its potential consequences.
To improve oncologic outcomes and tumor regression, one of the standard treatment options for locally advanced rectal cancer includes preoperative (chemo)radiotherapy, surgical resection (with or without ostomy), and adjuvant chemotherapy for patients with high-risk features [2][3][4][5].
It is undeniable that the diagnosis and treatment of rectal cancer can negatively affect patients' Health-related Quality of Life (HRQoL), a multidimensional construct that encompasses physical, emotional, cognitive, and social aspects and includes various environmental and personal factors [4,[6][7][8][9][10].
Psychological distress is associated with a poorer HRQoL [10,11].Rectal cancer and consequent cancer therapies can lead to changes in body image and self-representation, as well as fear about treatment outcomes and disease recurrence, which can exacerbate psychological distress such as anxiety and depressive symptoms [10][11][12][13].
Psychological aspects that can influence HRQoL in cancer patients include those related to affective experience and emotion recognition [10,14].Positive (e.g., pleasant emotional states, being active, alert, and enthusiastic) and negative (e.g., unpleasant involvement, distress, disgust, guilt) affectivity describe the affective experience and the emotional components of subjective well-being.A high level of positive affectivity promotes psychological well-being and psychosocial adjustment in cancer patients as well as a better HRQoL [10,15].In terms of emotion recognition, alexithymia, characterized by difficulties in identifying and describing subjective feelings and bodily sensations, as well as externally oriented thinking, has been associated with poorer health and HRQoL outcomes in populations affected by various medical conditions, including cancer [10,14,16,17].
Coping is a process of self-regulation that involves behavioral and cognitive strategies aimed at managing external and/or internal demands that exceed the individual's resources, such as cancer-related illness [18,19].Cancer patients who choose adaptive styles tend to have better physical health, fewer psychological problems and a better HRQoL [10,11,19,20].
Social support is an important external resource for the individual that positively influences the cognitive adjustment process, with low perception of social support being associated with poorer HRQoL in patients [6,21,22].
Although the impact of these psychological aspects on cancer patients HRQoL is known, no studies have specifically analyzed their combined role in the rectal cancer patients (RCPs) or included them in the main category of CRC without providing separate data.In particular, two recent prospective studies investigated HRQoL changes in RCPs treated with different combinations of preoperative chemoradiotherapy, but did not consider psychological predictors or effects [23,24].Of the only two studies that looked specifically at psychological distress in RCPs, one examined only psychological distress prior to chemoradiotherapy [13], while the other focused specifically on psychological and sexual distress and did not consider other psychological and clinical variables [12].
For these reasons, this exploratory study aims to evaluate the changes in HRQoL of RCPs during the different treatment phases and at a medium-term follow-up, and to investigate which physical and psychosocial factors better predict HRQoL at the different time points, i.e. after the appointment with the radiation oncologist where patients received the indication for treatment (T0 -diagnosis), after preoperative (chemo)radiotherapy (T1), after surgical resection (T2), and at followup one year after surgery (T3).

Study design and patient characteristics
This prospective observational cohort study was approved by the Institutional Review Board of the Hospital Ethics Committee (protocol number 0017109, procedure number CS2/1118) and conducted in accordance with the Declaration of Helsinki.Participants were recruited from April 2019 to April 2021 at the "Radiation Oncology Department" of the Hospital "Città della Salute e della Scienza" in Turin, Italy, after providing written informed consent.Inclusion criteria were: age >18years, a recent diagnosis of rectal cancer, indication for preoperative (chemo)radiotherapy and surgical resection, good knowledge of the Italian, and no severe cognitive or psychopathological disorders as reported in the patients' medical records.Radiation oncologists recruited patients who met the inclusion criteria, and then referred them to the clinical psychologist to complete the study assessment.
Sociodemographic, clinical, psychological and HRQoL variables were initially collected during the appointment with the radiation oncologist when patients received the indication for treatment (T0 − diagnosis).Psychological (except for alexithymia and trait affectivity) and HRQoL variables were collected again at least one month after the end of preoperative treatment (T1, on average 3 months after diagnosis), at least one month after surgical resection (T2, on average 6 months after diagnosis), and at the follow-up of at least one year after surgical resection (T3, on average 18 months after diagnosis).
The Hospital Anxiety and Depression Scale (HADS) is a 14-items selfreport instrument assessing psychological distress symptoms.The HADS total score ranges from 0 to 42, with a cut-off score of 15, with high scores indicating a high level of psychological distress [27,28].
The Positive and Negative Affect Scale (PANAS) is a self-report instrument on which participants rate the extent to which they experience positive (PA) and negative (NA) affects, from 1 (very slightly) to 5 (extremely).It contains two 10-item versions, one as a trait (PAN-AS_PAtr and PANAS_NAtr) and one as a state (PANAS_PAst and PAN-AS_NAst) variable [29].
The Toronto Alexithymia Scale (TAS-20) is a self-report instrument comprising 20 items rated on a five-point Likert scale.The TAS total score ranges from 20 to 100 with a cut-off point ≥61 indicating the presence of alexithymia [30].
The Multidimensional Scale of Perceived Social Support Scale (MSPSS) assesses perceived support with 12 items rated on a seven-point Likert scale.Scores range from 12 to 84, with high scores indicating a greater perception of support [32].

Statistical analysis
Statistical analyses were performed using the Statistical Package for Social Sciences − 28.0 (IBM SPSS Statistics for Macintosh, Armonk, NY, USA: IBM Corp.).Descriptive statistics summarized collected variables for the different time points.All variables were normally distributed (absolute values for skewness and kurtosis below 3.0 and 8.0 respectively).The Mann-Whitney U test and Fisher's Exact Test were used for baseline comparisons between completers and dropouts.Repeatedmeasures analyses were used to assess changes in variables over time, applying the Greenhouse-Geisser correction when sphericity was violated.In case of significant main effects, post-hoc analyses with Bonferroni correction were performed for significant main effects, to assess differences between each time point and the previous one.

Demographic and clinical characteristics
Forty-three RCPs (two-thirds men) with a mean age of approximately 62 years (range 34-84 years) were enrolled in the study at T0 (Table 1).
Most patients were diagnosed as T3N2M0 (8th edition of the TNM staging system) and all but one patient received preoperative chemotherapy in addition to radiotherapy.After surgery, 38 patients (86.5 %) had an ostomy (permanent in 11 patients and temporary in 21 patients) and 17 (39.5 %) patients received adjuvant chemotherapy.
Of the 43 patients enrolled, 3 dropped out at T1, 3 at T2, and 6 at the T3 follow-up for medical or personal reasons.However, the betweengroup comparisons of sociodemographic, clinical and psychological variables at T0 showed no differences between completers and dropouts.

Clinical and psychological changes over time
Table 2 shows T0 (N = 43), T1 (N = 40), T2 (N = 37) and T3 (N = 31) descriptive data and the p values of the repeated measures ANOVAs, assessing the main effect of time for each variable.
In terms of psychological traits, we found a low level of alexithymia, with only 6 (14 %) patients scoring above the TAS-20 cut-off, and a low tendency to experience a negative affectivity (PANAS_NAtr).The PAN-AS_NAst did not change over time, while the PANAS_PAst statistically increased between T2 and the T3 follow-up (post-hoc contrast: F(1,30) = 16.56,p < 0.001).
The MSPSS indicates a very high level of perceived social support at all the assessment time points.The Mini-MAC showed that Fighting Spirit and Helplessness/Hopelessness were the most and least utilized coping styles, respectively, while Anxious Preoccupation statistically decreased over time (post-hoc contrasts: T0 vs. T1: F(1,30) = 8.19, p = 0.008; T1 vs. T2: F(1,30) = 5.17, p = 0.030).

Discussion
The aim of the present exploratory longitudinal study was to evaluate changes in HRQoL of RCPs during cancer treatment, i.e. after diagnosis, after preoperative (chemo)radiotherapy and after surgical resection, and at a medium term follow-up (one years after surgery), and to assess which physical and psychosocial factors better predict HRQoL in the different time points.Deepening the understanding of the positive and negative predictive factors for patients' HRQoL at different phases could improve screening programs for early detection and intervention.
Most previous studies referred to the broader population of CRC patients and did not provide separate data focusing RCPs.Therefore, we performed the T0 assessment on 43 RCPs who had just received the diagnosis and treatment program.Consistent with two recent studies of CRC patients [33,34], HRQoL was preserved at this time point and patients had few physical symptoms.The main symptoms included intestinal and pain symptoms such as blood and mucus in the stool, flatulence, high stool frequency and buttock pain, which were directly associated with locally advanced rectal cancer [2,3].Overall preserved HRQoL at T0 was associated with moderate levels of psychological distress, as in the only other study that examined psychological distress in RCPs before starting active treatments [13].In our study, RCPs after diagnosis also showed high levels of health anxiety.The high level of health anxiety and psychological distress may be due to the initial burden due to cancer diagnosis and concern about the side effects of preoperative treatments, in particular those related to radiotherapy, which cancer patients are least aware of [35,36].
The most recent longitudinal studies in CRC patients suggested an improvement in HRQoL over time [33,34,37].However, all of these studies recruited patients who had already undergone major cancer treatments [33,34,37].When assessing changes since diagnosis, our data showed that HRQoL deteriorated significantly during the active treatment phases, particularly after surgery, before improving again at medium-term follow-up.These results are consistent with the only studies we are aware of comparing HRQoL of CRC patients [38] and RCPs [23] before and after surgery, which showed similar deterioration after surgery and subsequent improvement after one year.
The decline in HRQoL during active treatment came with a functional deterioration in body image and a general symptoms' worsening over the course of treatments, particularly in relation to the urinary system, the mouth area, and sexual symptoms (QLQ-CR29).Specifically, urinary and sexual symptoms increased after preoperative (chemo) radiotherapy as a possible side effect, while sexual interest worsened after surgery, probably due to the consequences of resection [4,7,8].Although physical symptoms increased, health anxiety improved over time, decreasing significantly after preoperative (chemo)radiotherapy.This improvement after preoperative (chemo)radiotherapy could further suggest that the high level of health anxiety at diagnosis could be partially due to the worry about the effects of radiotherapy [35,36].Similarly, the use of the Anxious Preoccupation coping style decreased over the course of the active treatments.
Also psychological distress decreased after preoperative treatments, but it increased again after surgery, probably due to adjustment to postoperative conditions (e.g., ostomy management) or to eventual adjuvant therapy [12,34,37].The only other study that assessed psychological distress in RCPs prior to preoperative treatment reported an overall decrease in psychological distress over time, although the mean scores seemed to confirm our fluctuating trend [12].
At follow-up, after the functional deterioration and worsening of symptoms that occurred during the course of treatment, there was a general improvement with a reduction in urinary and mouth area symptoms and a functional improvement in body image and sexual interest.In terms of psychosocial variables, psychological distress did not change significantly between T2 and follow-up, but patients experienced an increase in positive affect.The overcoming of the active treatment phase and the reduction of the side effects of those treatments leads to a progressive improvement in physical and mental health which results in an improvement in the HRQoL [34].
The explorative analyses conducted to evaluate possible positive and negative predictive factors suggested that physical and psychosocial factors have a different weight in impacting HRQoL during the different phases.At diagnosis, intestinal symptoms and trait negative affect negatively predicted HRQoL.After preoperative treatments, HRQoL was

Table 2
Repeated measures ANOVAs on Health-Related Quality of Life (QLQ-C30) at diagnosis (T0), after preoperative treatments (T1), after surgical resection (T2)) and at follow-up (T3; N = 31).significantly explained by intestinal and urinary symptoms at that time point and by the pain symptoms experienced at diagnosis.After surgery, HRQoL was significantly explained by psychological distress and mouth symptoms at that time point, and by the adoption of the fatalism coping style after the preoperative treatment.Similarly, at follow-up, HRQoL was mainly explained by psychological distress and residual clinical symptoms at that time point (in particular, pain and mouth area symptoms), and by the adoption of the fatalism coping style after the preoperative treatment.On the one hand, these data confirm the strong influence of physical symptoms on HRQoL in RCPs [8,38].However, this seems to be particularly the case at diagnosis and during active treatments, when cancer-related symptoms (i.e., intestinal and/or pain symptoms) and treatment-related physical side effects are the most important predictive factors.On the other hand, the data suggest that although psychological variables appear to have a smaller concurrent effect in the early phases, psychological reaction at these early phases has a higher weight in predicting RCPs' HRQoL after active treatments and at medium-term.Indeed, a greater use of fatalism after preoperative (chemo)radiotherapy positively predicted HRQoL after surgery and at the one-yearafter-surgery follow-up.This tendency towards a resigned and stoic attitude towards the disease and an external locus of control prior to surgery could be an indicator of greater acceptance and confidence in treatment, which could then translate into better HRQoL outcomes [10,11,19,20].In contrast, greater difficulty in acceptance and adaptation, which may also result in the persistence of high levels of psychological distress after surgery, becomes the factor that plays a greater role in explaining HRQoL after the end of active treatments and at mediumterm, along with long-term treatment-related side effects (such as pain and mouth symptoms).

Study limitations
The main limitation of the present study is the small sample size, which reduces the power of the analyses, potentially affecting some of the findings of the study.The COVID-19 pandemic not only hindered the recruitment and subsequent reassessment of patients, but also made access to combined-modality cancer treatments more difficult, leading to a decrease in the number of patients.Future longitudinal studies with a larger sample of RCPs are needed to further assess the impact of rectal cancer and the different treatments on patients' QoL.

Clinical implications
From a clinical perspective, our findings emphasise that multiple physical and psychological factors play a role in the changes in patients' HRQoL in response to cancer diagnosis and treatments.Overall, these data suggest the need for bio-psycho-social assessment of RCPs from the communication of diagnosis, through all subsequent phases of the treatment process to follow-up, as each phase has physical and psychological specificities.Based on these specificities, support services should be tailored to both the individual patient and the treatment phase, in particular by implementing multidisciplinary and multimodal preventive and pre-habilitation interventions not only before surgery [39,40], but even better immediately after diagnosis to improve both cancer-related reactions and HRQoL and psychological health in the medium term.

Conclusions
The findings of this study showed an overall worsening of HRQoL in RCPs from diagnosis to one month after surgical resection and an improvement from that time to follow-up, one year after surgery.In addition to surgery, preoperative (chemo)radiotherapy seemed to be a crucial step from both a psychological and physical point of view.This is because not only the side effects, especially those related to the urinary system, are among the physical symptoms that significantly worsen HRQoL one month after preoperative (chemo)radiotherapy, but it is also the treatment that worries patients the most and contributes to increasing health anxiety and psychological distress after diagnosis.Psychological distress and coping style should therefore be monitored throughout the course of treatment, as at the end of active cancer treatments and at medium-term follow-up, psychological adjustment to the diagnosis of rectal cancer appears to explain HRQoL more than physical symptoms.Psychological programs should therefore promote the early adoption of active coping styles and prevent psychological distress to achieve better HRQoL in the medium term.

Fig. 1 .
Fig. 1.Final models of the explorative hierarchical multiple regressions on the Health-Related Quality of Life (QLQ-C30) at the different time points.Only statistically significant predictors were shown with their β-value.The dashed line indicates the only positive predictive factor.

Table 1
Sociodemographic and clinical characteristics at diagnosis.

Table 3
Hierarchical multiple regressions with Health-Related Quality of Life (QLQ-C30) at the different times as dependent variables.